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Psychophysiological effects and dose equivalence of zopiclone and triazolam administered to healthy volunteers. Methodological considerations.
1. Dose-equivalence studies of zopiclone and triazolam were carried out. 2. Zopiclone (6.25, 8.75 and 11.25 mg), triazolam (0.1875, 0.375 and 0.5 mg) and placebo were given in the morning to 14 healthy male volunteers aged 20-25 years under double-blind conditions according to an incomplete block design. Each patient received three of the seven possible treatments at intervals of at least 1 week. Subjects were evaluated using physiological measures, rating scales and memory tasks before and 1.5 and 4.5 h after drug administration. 3. The sedative and amnestic effects of zopiclone were qualitatively similar to those of triazolam, with the highest dose of each having the greatest effect. 4. On the basis of the digit symbol substitution test, 10 mg of zopiclone is equivalent to 0.5 mg of triazolam. Methodological problems of the experimental design of dose-equivalence studies are discussed.
Long term efficacy and withdrawal of zopiclone: a sleep laboratory study.
The purpose of this study was to evaluate the short, intermediate, and long-term (8 weeks) effectiveness, as well as the withdrawal effects of zopiclone 7.5 mg. Eleven chronic insomniacs participated in the study where both EEG sleep recordings and a subjective rating scale were used to evaluate drug effects. Zopiclone significantly decreased total wake time and nocturnal awakenings, and increased total sleep time and sleep efficiency. These effects were apparent from first treatment night and tolerance to the hypnotic effect did not develop over the 8 weeks of treatment. The subjective sleep questionnaire data showed significantly decreased sleep latency time but otherwise were consistent with the sleep laboratory findings. Zopiclone decreased the percentage of Stage 1 sleep but did not significantly alter the percentage of Stage 2 sleep, slow wave sleep or REM sleep. The withdrawal of zopiclone was associated with a return of sleep variables towards pre-treatment baseline values. Although 2 patients dropped out, 1 with a marked rebound insomnia and daytime anxiety during the first week of withdrawal, the other because of side-effects and poor hypnotic efficiency, no evidence of rebound insomnia was seen on the sleep EEG or subjective questionnaire data in the study population.
A dose-range finding study of zopiclone in insomniac patients.
Sixty insomniac patients participated in a controlled double-blind parallel group study designed to investigate the dose-response relationship of zopiclone. Following 1 day of treatment with placebo, patients were randomly assigned to 1 of 6 groups and received treatment for 7 days with either placebo, or flurazepam 30 mg, or zopiclone, 3.75 mg, 7.5 mg, 11.25 mg or 15 mg. Four patients were dropped from the study; two from the placebo group due to ineffectiveness and one each in zopiclone 11.25 mg and 15 mg groups due to side-effects. Flurazepam 30 mg significantly improved sleep induction and maintenance by comparison to placebo and was indistinguishable from zopiclone 7.5 mg or higher. Results of a self-administered sleep questionnaire found a predominantly linear relationship between the dose of zopiclone administered and the degree of sleep improvement. The greatest increment in improvement was generally obtained with 3.5 mg and 7.5 mg of zopiclone, with some additional benefit occurring with zopiclone 11.25 mg. Clinicians' global impressions showed that the severity of illness clearly decreased in a dose related manner up to zopiclone 11.25 mg. Although zopiclone was well tolerated at 3.75 mg and 7.5 mg, an increase in side-effects occurred at 11.25 mg and 15 mg, which favours the use of 7.5 mg zopiclone as the optimum dose for most patients, although certain patients may benefit from a higher dose of the drug when well tolerated.
Immediate and overnight effects of zopiclone 7.5 mg and nitrazepam 5 mg with ethanol, on psychomotor performance and memory in healthy volunteers.
The effects of ethanol (0.2-0.4 g/kg) taken in conjunction with a single nocturnal dose of zopiclone 7.5 mg or nitrazepam 5 mg, on the early morning performance were investigated by means of psychomotor tests in 9 female volunteers. While there was no noticeable difference in the Choice Reaction Time (CRT) for any of the drug-ethanol combinations and ethanol alone, the zopiclone combination appeared to be initially more sedative in the Critical Flicker Fusion test (CFF). Both drug combinations impaired short-term memory and induced retrograde amnesia to the same extent, although only the nitrazepam-ethanol treatment caused further anterograde amnesia as compared to ethanol alone. Finally, both drug-ethanol combinations exhibited equivalent hypnotic properties as assessed by the Leeds Sleep Evaluation Questionnaire (LSEQ) without any more residual effects than with ethanol alone. These results suggest neither zopiclone, nor nitrazepam potentiate the effects of ethanol at the doses used.
A multi-centre open study in general practice to evaluate the efficacy and acceptability of zopiclone 7.5 mg nocte in patients requiring the prescription of an hypnotic.
This was an open study of the efficacy and acceptability of zopiclone 7.5 mg nocte as a somnifacient. The study population comprised 108 insomniac patients (70 female, 38 male) aged 22-74 years who received zopiclone 7.5 mg for 7 consecutive nights. Based on subjective sleep assessments, zopiclone reduced the patients' difficulty in falling asleep, increased the number of hours slept and decreased the number of nocturnal awakenings (p less than 0.001). The majority of patients reported sleeping well or very well. The quality of sleep improved (p less than 0.0001), and the incidence of waking earlier than desired decreased (p less than 0.001), with respect to baseline, after receiving zopiclone. Physicians rated efficacy as good or very good in the majority of patients. Zopiclone was efficacious both in patients who had not previously received hypnotic therapy (n = 37) and in patients who transferred directly to zopiclone from a benzodiazepine hypnotic (n = 26). Whilst receiving zopiclone, patients reported feeling better in the morning than they did prior to treatment (p less than 0.004); 78% expressing satisfaction with zopiclone as an hypnotic. Physicians reported zopiclone treatment to be without side-effects in the majority of patients. In conclusion, zopiclone appears to be an effective and well-tolerated hypnotic that may play a role in the treatment of insomnia in the general population.
Actions and interactions of hypnotics on human performance: single doses of zopiclone, triazolam and alcohol.
Actions and interactions with ethanol (0.8 g/kg) of triazolam (TRZ, 0.25 mg) and zopiclone (ZOP, 7.5 mg) on performance and memory were studied with 12 healthy young subjects. The randomized double-blind and crossover test sessions were carried out at 1-week intervals. Each time a set of performance tests and self-assessments on visual analogue scales were done before the treatment and 1.5, 3, 4.5, 6 and 8 h after it. The clinical test for drunkenness (CTD) was done 2 and 5 h after drug intake. Venous blood was sampled after each set of tests. Both TRZ and ZOP impaired coordinative and reactive skills, but not peripheral attention or body balance. They also impaired cognitive test performance (digit substitution, symbol copying), and lowered flicker fusion threshold. The psychomotor effects of the two hypnotics and measures of subjective sedation peaked at 1.5 and 3 h. Spatial memory was impaired by TRZ at 4.5 h. Cognitive tests and tracking were most sensitive to alcohol. Furthermore alcohol impaired both motor and vestibular aspects of the CTD while both ZOP and TRZ alone had only minor effects. Alcohol enhanced and prolonged the effects of both hypnotics without modifying their plasma concentrations. Drug-alcohol interactions were mainly additive though more obvious with TRZ. Interactions were evident also on the CTD. The hypnotics were free from residual psychomotor and cognitive effects at 8 h even after the coadministration of alcohol. It is concluded that ZOP and TRZ have a mainly additive interaction with alcohol but pharmacokinetic mechanisms do not seem to contribute essentially to this.
Post marketing surveillance of zopiclone: interim analysis on the first 10,000 cases in a clinical study in general practice.
The tolerance of zopiclone, a hypnotic belonging to a new chemical group, the cyclopyrrolones, was studied in a follow-up trial in 23,000 insomniac outpatients treated for 3 weeks. The results from the interim analysis of the first 10,000 cases confirm the efficacy and safety of zopiclone under usual prescribing conditions. The average daily dose of zopiclone was 0.97 +/- 0.21 tablet (7.275 +/- 1.575 mg). The study population included 63.1% of female and 36.9% of male patients; the mean age was 52.3 +/- 16.6 years. 93.1% of the patients completed the trial. 8.2% of the patients experienced adverse reactions which resulted in drug discontinuation in only 2.8% of cases. In the global evaluation, the efficacy was rated excellent or good in more than 80% of the patients.
Zopiclone, the third generation hypnotic: a clinical overview.
Effective and safe hypnotics exist especially since the introduction of benzodiazepines (BZD) which appeared to bring major advantages over barbiturates. Ideally a new hypnotic should induce and maintain sleep without producing residual effect during the day and should be devoid of abuse and dependence potential. Zopiclone is a new hypnotic belonging to the cyclopyrrolone chemical class. Its elimination half-life is 5 to 6 h, no accumulation exists upon repeated administration, and its pharmacokinetic profile is not substantially modified in elderly and renal failure patients. Placebo-controlled studies have shown that zopiclone 7.5 mg is an effective hypnotic, and that it can improve all sleep variables in insomniacs. Its effects on sleep stages differ from those observed with BZD hypnotics: REM sleep is substantially unaffected by zopiclone and slow wave sleep is either unaffected or increased. Objective and subjective measurements during the day after bedtime administration of zopiclone, showed lack of residual effects and no residual impairment of cognitive functions. Zopiclone discontinuation is not accompanied by rebound effect and relevant withdrawal symptoms. Specific "craving effect" studies in alcoholics did not show an abuse potential for zopiclone. Side-effects are represented mainly by bitter taste and dry mouth with a minimal incidence of CNS depressant effects. Studies on the effects of zopiclone on respiratory functions failed to show detrimental effects. Efficacy and safety data on zopiclone suggest that this new drug can represent a useful alternative to existing hypnotics.
A comparative study of zopiclone and triazolam in patients with insomnia.
Zopiclone, a cyclopyrrolone derivative, was compared with triazolam in a double-blind, randomized, parallel group study in general practice patients suffering from insomnia. Both drugs were found to be effective compared to baseline assessment in that they increased the number of hours of sleep, reduced the number of nocturnal wakenings and reduced the latency of falling asleep. In addition, both drugs improved patients' condition following awakening, with zopiclone showing slight superiority. In both treatment groups, there was a transient period of poor sleep after withdrawal of the drug, and one patient in each group withdrew from the study for this reason. There were no serious adverse reactions during the trial.
Efficacy and safety of zopiclone and triazolam in the treatment of geriatric insomniacs.
Most studies with zopiclone, a cyclopyrrolone derivative with a short elimination half life (5 h) have compared its hypnotic activity with that of long elimination half life molecules. In this double-blind study in geriatric patients, drugs were administered during 3 weeks and the therapeutic effects of zopiclone at optimal dosage (5 or 7.5 mg) were compared to those of triazolam (0.125 or 0.25 mg). After a 3 day single-blind washout period, placebo responders were excluded and 48 patients were thereafter treated with either placebo (Tétreault et al., 1965), zopiclone or triazolam (Pegram et al., 1980). The initial dosage was increased when indicated at the end of the first week and kept constant thereafter. At the end of the third week of double-blind treatment, a 4 day single-blind placebo washout was performed to assess drug withdrawal effects. Results confirmed the safety and efficacy of both drugs over placebo during active administration. Hypnotic activity was maximal at 7.5 mg of zopiclone and 0.25 mg of triazolam. Drug efficacy was found constant over the 3 week administration both for triazolam and zopiclone. During withdrawal, no true rebound effect was demonstrated but the active drugs were significantly worse than placebo during the first day for sleep onset duration, sleep soundness and quality of sleep. With triazolam some effects persisted up to the third day of withdrawal.
Zopiclone versus triazolam in insomniac geriatric patients: a specific increase in delta sleep with zopiclone.
This double-blind study was performed on 10 aged insomniac patients who received, during 15 days, either triazolam (0.25 mg) or zopiclone (7.5 mg) at bed time. This in-patient period was bounded by two ambulatory periods of 5 days each, and two in-patient periods of 3 days each, during which the patients received a placebo tablet at bed time. Thirteen sleep recordings per patient were performed before (3 nights), upon initiation of active treatment (3 nights), at the end of the active treatment period (3 nights) and during the following 3 "withdrawal" nights. A clear improvement of sleep patterns was observed with both drugs, although opposite effects on delta sleep were observed, namely a decrease with triazolam and an increase with zopiclone. A carry-over effect of the enhancement of delta sleep by zopiclone took place during the first 3 withdrawal nights. As is well known, sleep problems become increasingly common with age. Epidemiological studies show that although they only represent 11% of the population. Americans over 60 years old are prescribed about 40% of sleeping pills (Mendelson, 1980). Disturbed sleep in this population is often associated with medical disorders or induced by drugs like beta-adrenergic blockers. It must be admitted, however, that, possibly due to the association with medical or situational problems there have been only few attempts to assess the efficiency of hypnotic drugs in elderly insomniac patients. These are the reasons why in this study the effectiveness of zopiclone was compared to that of triazolam in insomniac patients aged over 60 years.(ABSTRACT TRUNCATED AT 250 WORDS)
A comparison of the efficacy, tolerance and residual effects of zopiclone, flurazepam and placebo in insomniac outpatients.
A double-blind randomized parallel group design was used to compare the tolerance and efficacy of zopiclone 7.5 mg, flurazepam 30 mg and placebo taken each night for 3 weeks in a group of 24 out-patients complaining of sleep disturbance. Analogue rating scales were used to assess the efficacy of the treatments while tolerance and residual effects were measured weekly using a battery of performance tests (Critical Flicker Fusion Threshold, Choice Reaction Time, Letter Cancellation and Digit Span). Physical and clinical examinations, including ECG and EEG, were conducted before and after the experimental period and spontaneously reported side-effects were recorded. Analysis of variance on 24 completed cases (8 patients in each treatment group) showed both active treatments to be significantly better than placebo in shortening sleep onset latency. Flurazepam increased the duration of sleep and produced a "hangover" of impaired psychomotor function. Zopiclone had no observable effect on early morning performance and was free from residual sedative activity. The lack of residual effects with zopiclone 7.5 mg, at a dose shown to be clinically effective, suggests its use in ambulant or out-patient populations where daytime sedation could interfere with every day activities.
The effect of zopiclone 7.5 mg on the sleep, mood and performance of shift workers.
Shift workers often complain of an inability to sleep well between successive periods of work. The purpose of the study was to assess the influence of zopiclone, hypnotic with minimal residual effects, on work-time performance and mood. In this double-blind, cross-over study, 12 healthy male volunteers, aged between 18 and 35 years, from the Royal Air Force, working 12 h shifts in radar installations, were given zopiclone 7.5 mg at bed time or placebo for 2 shift cycles in a randomized order. Zopiclone significantly improved night time sleep, with a trend towards improvement of day-time sleep. There was no effect on psychomotor performance (assessed by critical flicker fusion threshold, choice reaction time and digit symbol substitution test) nor on mood (assessed by visual analogue scales). It can be concluded that zopiclone is a safe hypnotic which can be used by shift workers without impairing work time performance.
Comparative study of the effects of zopiclone and placebo on respiratory function in patients with chronic obstructive respiratory insufficiency.
Long-term administration of zopiclone in 6 patients with severe chronic obstructive respiratory insufficiency with stable ventilatory function did not demonstrate any depressant action on respiratory blood gases recorded during the daytime and in ambient air. The sedative action of this agent was manifested by a modest decrease in ventilatory response parameters which, however, was not statistically significant. Polysomnographic recordings did not reveal any worsening of desaturation periods both with respect to incidence and amplitude. There was a non-significant trend towards an increase in the number of obstructive apnoea episodes without any notable ventilatory impact.
Effect of zopiclone and midazolam on sleep and EEG spectra in a phase-advanced sleep schedule.
Midazolam (15 mg), a benzodiazepine (BDZ) hypnotic, and zopiclone (7.5 mg), a non-BDZ hypnotic, were administered to young, healthy subjects prior to bedtime. They went to bed at 2300 hours after taking placebo (PL-23), and then on three occasions at 1900 hour after taking placebo (PL-19) or one of the hypnotics. Advancing bedtime by 4 hour increased the combined value of waking, stage 1, and movement time. Compared to PL-19, both drugs reduced sleep latency and stage 3, and increased stage 2. Spectral analysis of the EEG in non-rapid-eye-movement sleep revealed a declining trend of power density in the low-frequency range in the course of the night. Activity in the 1 to 10 Hz range was markedly depressed by the two hypnotics, whereas activity in the spindle range (11 to 14 Hz) was augmented. The former changes persisted throughout the 12-hour recording period. The fact that both hypnotics bind to BDZ receptors could be responsible for the similar effects on the EEG spectra.
Zopiclone (Imovane): evaluation in general practice.
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